The overall long range goal of this program project is to generate novel data on the causal mechanisms of mental stress ischemia (MSI), to identify new endophenotypes susceptible to MSI, to determine the clinical importance of MSI in a diverse and contemporary patient population with stable coronary artery disease (CAD), and to identify genotype variants that may put individuals at increased risk for MSI. This program project will consist of three projects and three cores. We will study 650 participants with broadly defined CAD. We propose to examine rain, genetic, vascular, hormonal, and behavioral correlates of MSI and their potential role in future cardiac events. This project will lead to new knowledge related to the mechanisms of MSI which could have tremendous influence on the ability to successfully treat this phenomenon. Project 1: Mental Stress Ischemia: Prognosis and Genetic Influences. Dr. Sheps, PI, will study the relationship between MSI and cardiovascular outcomes and the role of genetic factors on MSI susceptibility. He will perform exercise and mental stress testing, genetic studies and follow up studies on all 650 patients. Project 2: Vascular Responses During Mental Stress. Dr. Arshed Quyyumi, PI, will study vascular mechanisms, i.e., abnormal vascular reactivity and pro-inflammatory responses as they relate to mental stress and MSI. He will examine peripheral vascular function in the same cohort of patients during mental stress, and coronary vascular responses in a sub group of 80 patients. Studies will be repeated at year two of follow-up to assess potential influences on disease progression. Project 3: Depression and Mental Stress Ischemia: Brain Mechanisms. Dr. Viola Vaccarino, PI, will study brain mechanisms, with a focus on neurobiological pathways related to depression. She will examine the link between depression and MSI in the whole PPG population and will perform brain imaging and neuroendocrine assessments in a subgroup of 160 patients. These studies will be supported by an Administrative and Laboratory Core, an Imaging Core, and a Biostatistics and Data Management Core. The knowledge gained from this program project should lead to PUBLIC HEALTH RELEVANCE: This research has potential to identify genetic variants, vascular abnormalities and neuropsychological features that place individuals at high risk for development of mental stress ischemia and therefore adverse outcomes. If successful, this research will contribute in significant ways to the development of the new field of personalized medicine in which individuals at high risk can be identified early in the disease process and targeted for preventative interventions.